The present invention relates to the field of ophthalmic drug delivery. More particularly, this invention relates to enhancement of the penetration of ophthalmic drugs and other therapeutic agents through the cornea of the eye.
In order for an ophthalmic drug to be therapeutically effective, it is generally necessary for the drug to penetrate the cornea and be taken up in the aqueous humor, ciliary processes and other tissues in the eye. There are notable exceptions to this general rule, such as drugs or drug products which produce a therapeutic effect by acting on the exterior surface of the cornea (e.g., drugs or drug products useful in improving ocular comfort and/or treating dry or irritated eyes). However, the treatment of conditions involving physiological mechanisms within the eye (e.g., glaucoma, diabetic retinopathy, cataracts, etc.) generally does require the movement of topically applied ophthalmic drugs through the cornea.
In order for a drug to pass through the cornea, it must penetrate three layers of tissue, namely, the epithelium, stroma and the endothelium. Except for highly lipophilic drugs, the epithelium is the main barrier to drug penetration of the cornea. Penetration of the stroma basically involves diffusion of the drug through a barrier which is approximately 360 microns thick. There are currently no known methods of enhancing drug penetration through the stroma or endothelium. However, it is possible to enhance the penetration of drugs through the epithelium, and thereby enhance the overall absorption of drugs applied topically to the eye. The present invention is directed to such enhancement.
There have been prior attempts to enhance the penetration of drugs through the corneal epithelium. The goal of such attempts has generally been to enhance penetration of drugs through the corneal epithelium to an optimal point at which the stroma alone controls drug transport through the cornea. The prior attempts have included use of chemical agents to enhance the penetration of drugs through the epithelium. It has been reported that benzalkonium chloride (BAC), bile salts, dimethyl sulfoxide (DMSO), ethylenediamine tetraacetate (EDTA) and 1-dodecylazayl-cycloheptan-2-one (AZONE.RTM.) enhance the corneal penetration of certain drugs. The following publications may be referred to for further background concerning the use of such agents to enhance corneal penetration: Acta Ophthalmological, Vol.53, p.335 (1975); J. Pharm. Pharmacol., Vol.39, p.124 (1987); Chem. Abstracts, Vol.106, 125931t, p.402 (1987); Journal of Pharmaceutical Sciences, Vol.77, No.1 (Jan.,1988); and Investigative Ophthalmology and Visual Science, Vol.29, No.2 (Feb.,1988). Notwithstanding such prior attempts, there continues to be a need for a means of safely and effectively enhancing the penetration of drugs through the cornea.